Elucidating the Link Between the Environment, the Brain and Depression: Genetic and Epigenetic Mechanisms

The development and maintenance of depression is influenced by a combination of genetic and environmental factors, as well as their interactions. In recent decades, a number of candidate genes involved in stress-related systems have been implicated in major depressive disorder, shedding light on the genetic contributions to depression. Further, the study of epigenetic mechanisms has provided a potential mechanism by which the expression of genes implicated in depression are shaped by the environment, offering a bridge between environmental (e.g., early life adversity) and genetic factors. However, relative to adulthood, our knowledge of the genetic and epigenetic mechanisms of depression in childhood and adolescence remains limited. The current thesis aimed to address several gaps in our understanding of the genetic and epigenetic basis of depression in childhood and adolescence, while simultaneously exploring novel epigenetic methodology, which, in turn, could inform our understanding of depression across the entire lifespan. The projects that are described in this thesis used a variety of measures, including longitudinal ACE modelling of twin cohort data, (functional) magnetic resonance imaging, peripheral assessments of DNA methylation and in vivo assessment of epigenetic processes using positron emission tomography. In study 1, we showed in a longitudinal cohort of 1344 twins that the association between externalizing symptoms at the preschool age and internalizing symptoms in early adolescence was essentially accounted for by genetic factors, suggesting a shared genetic vulnerability to externalizing and internalizing symptoms that is stable throughout childhood. In study two, we examined the association between DNA methylation at key genes within the serotonin and HPA axis systems (i.e., SLC6A4 and FKBP5 respectively) in 25 adolescents with major depressive disorder and 20 healthy controls. We found associations between DNA methylation, diagnostic status and frontolimbic structure/function that both converged with and diverged from findings in adults. In study three, we examined the link between childhood adversity, epigenetics and depression vulnerability while simultaneously addressing a common limitation in the epigenetic literature also present in study 2, the reliance on peripheral epigenetic measures. Using the novel [11C]Martinostat tracer in combination with positron emission tomography, we assessed levels of histone deacetylase (HDAC) in vivo. We found, in a sample of 14 healthy adult males, that HDAC density was associated with depressive symptoms and neuroticism in key frontolimbic regions. We found no association between early life adversity and HDAC density. The results from the projects described in this dissertation may offer novel contributions to our understanding of the epigenetic and genetic basis of depression across childhood and adolescence, and validate the use of the novel [11C]Martinostat in the study of depressive symptoms and personality traits relevant to depression

Impact of early environment on children's mental health : lessons from DNA methylation studies with monozygotic twins

Over the past decade, epigenetic analyses have made important contributions to our understanding of healthy development and a wide variety of adverse conditions such as cancer and psychopathology. There is increasing evidence that DNA methylation is a mechanism by which environmental factors influence gene transcription and, ultimately, phenotype. However, differentiating the effects of the environment from those of genetics on DNA methylation profiles remains a significant challenge. Monozygotic (MZ) twin study designs are unique in their ability to control for genetic differences because each pair of MZ twins shares essentially the same genetic sequence with the exception of a small number of de novo mutations and copy number variations. Thus, differences within twin pairs in gene expression and phenotype, including behavior, can be attributed in the majority of cases to environmental effects rather than genetic influence. In this article, we review the literature showing how MZ twin designs can be used to study basic epigenetic principles, contributing to understanding the role of early in utero and postnatal environmental factors on the development of psychopathology. We also highlight the importance of initiating longitudinal and experimental studies with MZ twins during pregnancy. This approach is especially important to identify: (1) critical time periods during which the early environment can impact brain and mental health development, and (2) the specific mechanisms through which early environmental effects may be mediated. These studies may inform the optimum timing and design for early preventive interventions aimed at reducing risk for psychopathology

The neuroscience of sadness: A multidisciplinary synthesis and collaborative review

Sadness is typically characterized by raised inner eyebrows, lowered corners of the mouth, reduced walking speed, and slumped posture. Ancient subcortical circuitry provides a neuroanatomical foundation, extending from dorsal periaqueductal grey to subgenual anterior cingulate, the latter of which is now a treatment target in disorders of sadness. Electrophysiological studies further emphasize a role for reduced left relative to right frontal asymmetry in sadness, underpinning interest in the transcranial stimulation of left dorsolateral prefrontal cortex as an antidepressant target. Neuroimaging studies – including meta-analyses – indicate that sadness is associated with reduced cortical activation, which may contribute to reduced parasympathetic inhibitory control over medullary cardioacceleratory circuits. Reduced cardiac control may – in part – contribute to epidemiological reports of reduced life expectancy in affective disorders, effects equivalent to heavy smoking. We suggest that the field may be moving toward a theoretical consensus, in which different models relating to basic emotion theory and psychological constructionism may be considered as complementary, working at different levels of the phylogenetic hierarchy.Fil: Arias, Juan A.. Swansea University; Reino Unido. Universidad de Santiago de Compostela; EspañaFil: Williams, Claire. Swansea University; Reino UnidoFil: Raghvani, Rashmi. Swansea University; Reino UnidoFil: Aghajani, Moji. No especifíca;Fil: Baez, Sandra. Universidad de los Andes; ColombiaFil: Belzung, Catherine. Universite de Tours; FranciaFil: Booij, Linda. Concordia University Montreal; CanadáFil: Busatto, Geraldo. Universidade de Sao Paulo; BrasilFil: Chiarella, Julian. Concordia University Montreal; CanadáFil: Fu, Cynthia. University Of East London; Reino UnidoFil: Ibañez, Agustin Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt; Argentina. Universidad Adolfo Ibañez; Chile. Universidad Autónoma del Caribe; ColombiaFil: Liddell, Belinda J.. University of New South Wales; AustraliaFil: Lowe, Leroy. No especifíca;Fil: Penninx, Brenda W.J.H.. No especifíca;Fil: Rosa, Pedro. Universidade de Sao Paulo; BrasilFil: Kemp, Andrew H.. Universidade de Sao Paulo; Brasil. Swansea University; Reino Unid

Pre-nucleation clusters as solute precursors in crystallisation

Crystallisation is at the heart of various scientific disciplines, but still the understanding of the molecular mechanisms underlying phase separation and the formation of the first solid particles in aqueous solution is rather limited. In this review, classical nucleation theory, as well as established concepts of spinodal decomposition and liquid–liquid demixing, is introduced together with a description of the recently proposed pre-nucleation cluster pathway. The features of pre-nucleation clusters are presented and discussed in relation to recent modifications of the classical and established models for phase separation, together with a review of experimental work and computer simulations on the characteristics of pre-nucleation clusters of calcium phosphate, calcium carbonate, iron(oxy)(hydr)oxide, silica, and also amino acids as an example of small organic molecules. The role of pre-nucleation clusters as solute precursors in the emergence of a new phase is summarized, and the link between the chemical speciation of homogeneous solutions and the process of phase separation via pre-nucleation clusters is highlighted

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Combinations of single-top-quark production cross-section measurements and vertical bar f(LV)V(tb)vertical bar determinations at root s=7 and 8 TeV with the ATLAS and CMS experiments

This paper presents the combinations of single-top-quark production cross-section measurements by the ATLAS and CMS Collaborations, using data from LHC proton-proton collisions at = 7 and 8 TeV corresponding to integrated luminosities of 1.17 to 5.1 fb(-1) at = 7 TeV and 12.2 to 20.3 fb(-1) at = 8 TeV. These combinations are performed per centre-of-mass energy and for each production mode: t-channel, tW, and s-channel. The combined t-channel cross-sections are 67.5 +/- 5.7 pb and 87.7 +/- 5.8 pb at = 7 and 8 TeV respectively. The combined tW cross-sections are 16.3 +/- 4.1 pb and 23.1 +/- 3.6 pb at = 7 and 8 TeV respectively. For the s-channel cross-section, the combination yields 4.9 +/- 1.4 pb at = 8 TeV. The square of the magnitude of the CKM matrix element V-tb multiplied by a form factor f(LV) is determined for each production mode and centre-of-mass energy, using the ratio of the measured cross-section to its theoretical prediction. It is assumed that the top-quark-related CKM matrix elements obey the relation |V-td|, |V-ts| << |V-tb|. All the |f(LV)V(tb)|(2) determinations, extracted from individual ratios at = 7 and 8 TeV, are combined, resulting in |f(LV)V(tb)| = 1.02 +/- 0.04 (meas.) +/- 0.02 (theo.). All combined measurements are consistent with their corresponding Standard Model predictions.Peer reviewe